The long-term objective of this project is to identify lead compounds for the development of male contraceptive drugs. The project takes advantage of: 1) the observation that blocking meiotic recombination in spermatogenesis leads to apoptosis of the developing spermatocytes, and therefore sterility, 2) the high degree of homology of yeast and mammalian meiotic recombination proteins, 3) the observation that many mammalian genes involved in basic cellular functions can functionally substitute for the cognate yeast genes, and 4) the development of simple methods for replacement of yeast with mammalian genes, and 5) the development of simple methods for high throughput screening for interactions between small compounds and specific mammalians genes that are performing essential functions in yeast. In this Phase I applications we propose to replace five genes of yeast that are required for meiotic recombination with their human homologs. Identification of human meiotic recombination genes that can functionally replace the yeast homologs will provide a platform for a Phase II grant. In Phase II, we would perform high throughput screening to identify compounds that block function of the human meiotic genes. These compounds would be candidate male contraceptives, potentially capable of reversibly blocking spermatogenesis. PROPOSED COMMERCIAL APPLICATION: Years of research have failed to produce a male contraceptive drug. Most efforts have focused on hormone-based approaches. This project is designed to identify familes of compounds that should block spermatogenesis in ways less prone to the side effects that have thwarted the development of effective male contraceptives. One third of couples currently use male-based contraceptive approaches. Market research suggests there is broad interest in a male contraceptive drug.